Hobbs, Robin M.

Pandolfi, Pier Paolo

Oncotarget

Harvard University - DASH 

 Shape-shifting and tumor suppression by PLZF  (Article begins on next page)The Harvard community has made this article openly available.Please share how this access benefits you. Your story matters.Citation Hobbs, Robin M., and Pier Paolo Pandolfi. 2010. “Shape-shiftingand tumor suppression by PLZF.” Oncotarget 1 (1): 3-5.Accessed February 16, 2015 11:06:31 AM ESTCitable Link http://nrs.harvard.edu/urn-3:HUL.InstRepos:12406683Terms of Use This article was downloaded from Harvard University's DASHrepository, and is made available under the terms and conditionsapplicable to Other Posted Material, as set forth athttp://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA3 OncoTarget, May 2010 www.impactjournals.com/oncotarget/ www.impactjournals.com/oncotarget/                                                              OncoTarget,  May 2010Shape-shifting and tumor suppression by PLZF Robin M. Hobbs1 and Pier Paolo Pandolfi11 Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Departments of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.Correspondence to:  Pier Paolo Pandolfi, e-mail: ppandolf@bidmc.harvard.eduReceived: April 29, 2010,        Accepted: April 30, 2010,          Published: on line May 4, 2010Copyright: C 2010 Hobbs et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.The promyelocytic leukemia zinc finger (PLZF) tran-scription factor is directly implicated in tumor suppression although the relevant target genes remain poorly defined. Shi et al. now implicate smooth muscle α-actin and changes in cytoskeletal architecture as key downstream targets of PLZF in opposing cellular transformation.PLZF  is  a  transcriptional  repressor  belonging  to  the POZ-Krüppel (POK) family of transcription factors with critical roles in oncogenesis, development and stem cell maintenance  [1-7]. The  amino-terminal  POZ  domain  of PLZF  recruits  transcriptional  co-repressors  and  histone deacetylase  (HDAC)  activity  while  carboxy-terminal Krüppel-type zinc fingers mediate sequence-specific bind-ing to gene promoter elements; leading to stable repression of relevant target genes [8, 9]. PLZF was originally identi-fied from its involvement in chromosomal translocations with the RARA gene in cases of t(11;17) acute promy-elocytic leukemia (APL) [10]. Expression of the result-ing PLZF-RARα and RARα-PLZF fusion proteins drives acute leukemia development by disrupting expression of both  RARα  and  PLZF  target  genes  [5,  11-13].  RARα-PLZF retains DNA binding domains of PLZF but replaces the POZ domain with a transactivating domain from RARα resulting in activation rather than repression of PLZF target genes. Therefore, abrogation of PLZF function and mis-expression of PLZF target genes are thought to be critical for APL development [5]. Consistent with its role in APL, PLZF expression is associated with growth inhibition and cell cycle arrest through its ability to repress expression of a number of growth promoting and proto-oncogenic genes [14-16].Subsequent to its original characterization in the con-text of leukemia development, tumor suppressive functions have been attributed to PLZF in other cell types and tissues [17-19]. Using chicken embryonic fibroblasts (CEFs) as a model cell system, Shi et al. have previously demonstrated that PLZF opposes the transformation activity of a variety of cellular and viral oncogenes [20]. In terms of mechanism, the ability of PLZF to inhibit c-Myc function was associated with generation of this transformation-refractory state. In this issue, Shi et al. characterize smooth muscle α-actin as a novel PLZF target gene and link Ras-dependent changes in cytoskeletal architecture to PLZF-mediated inhibition of transformation. This novel mechanism thus represents an additional pathway by which PLZF is able to exert its tumor suppressive function (Figure 1). CommentaryFig. 1.  Pathways of Plzf-mediated tumor suppressionPLZF can oppose cellular transformation through multiple targets. PLZF expression in CEFs leads to repression of smooth  muscle  α-actin  expression  and  triggers  cells  to adopt a flattened, polygonal morphology distinct from the typical fibroblastic shape. This cell morphology is associ-ated with resistance to transformation induced by multiple distinct oncogenes. PLZF also inhibits c-Myc activity by tran-scriptional and post-translational mechanisms to oppose cell growth and transformation. Regulation of cytoskeletal archi-tecture and c-Myc by PLZF can be relevant to leukemia-initi-ating cell (LIC) function and stem cell maintenance.4 www.impactjournals.com/oncotarget/ OncoTarget, May 2010Oncogenic  stimuli  that  drive  cellular  transformation often trigger an accompanying remodeling of the cytoskele-ton that results in altered cell morphology and growth prop-erties [21]. Furthermore, the ability of tumor cells to invade surrounding tissue and ultimately metastasize is affected by changes in cell migration involving dynamic alterations to the cytoskeletal network [22]. Shi et al. make the criti-cal observation that expression of PLZF in CEFs induces a reorganization of the actin stress fiber component of the cytoskeleton and alters cell morphology from the typical spindle-shaped fibroblastic shape to a polygonal and flat-tened one. This morphological change was associated with a direct repression of smooth muscle α-actin expression by PLZF, suggesting that PLZF affects the cytoskeleton through modulation of the levels of specific structural com-ponents.  Furthermore,  expression  of  dominant  negative Ras (RasN17) blocked PLZF-mediated alterations to cell morphology indicating involvement of small GTPases such as Ras, Rac and Rho in this cytoskeletal rearrangement. Importantly, the ability of PLZF to affect cell morphology was linked to its ability to oppose the generation of trans-formed cell foci by distinct cellular and viral oncogenes; those  oncogenes  unable  to  revert  the  flattened,  polygo-nal phenotype of PLZF-expressing CEFs (e.g. myr-Akt, c-Myc) were successfully opposed by PLZF while those oncogenes that reverted the PLZF-induced cellular mor-phological changes (e.g. v-Src, v-Jun) did not have their transformation capabilities blocked by PLZF. These results thus define a connection between PLZF-induced changes to  cytoskeletal  architecture  and  PLZF  tumor  suppressor activity while underscoring the importance of cytoskeleton remodeling in oncogene-driven cellular transformation.Taken together, these results offer important insight into the role of PLZF in opposing oncogenesis and raise a number of interesting questions warranting further investigation. Namely, how do PLZF-mediated changes to the actin cyto-skeleton inhibit transformation and what are the relevant mechanisms by which certain oncogenes circumvent this? In addition, can this PLZF-driven cytoskeletal remodeling be translated into the context of tumor development where drastic alterations to the cytoskeleton occur, such as during epithelial-to-mesenchymal  transition  (EMT)  and  cancer cell invasion? Furthermore, while smooth muscle α-actin is identified as a direct target of PLZF, it remains to be shown whether reduced expression of this gene is entirely respon-sible for observed changes to the CEF actin cytoskeleton upon PLZF expression. The potential existence of alterna-tive PLZF target genes involved in cytoskeleton remodel-ing could extend this model of tumor suppression to other cell types where smooth muscle α-actin is not typically expressed. In addition, given the ability of PLZF to oppose c-Myc function at multiple levels in these CEF transforma-tion assays, it will be interesting to assess potential cross-talk between c-Myc, smooth muscle α-actin expression and cellular transformation. Finally, these studies can provide insight and raise new questions regarding the role of PLZF in both leukemia development and stem cell maintenance [2-5, 7]; do the fusion proteins of t(11;17) APL drive leu-kemogenesis  in  part,  through  opposing  PLZF-regulated cytoskeletal architecture and does this mechanism of PLZF action have a role in stem cell biology?REFERENCES1.  Barna M, Hawe N, Niswander L, Pandolfi PP. Plzf regulates limb and axial skeletal patterning. Nat Genet 2000; 25:166-172.2.  Buaas FW, Kirsh AL, Sharma M, McLean DJ, Morris JL, Griswold MD, de Rooij DG, Braun RE. Plzf is required in adult male germ cells for stem cell self-renewal. Nat Genet 2004; 36:647-652.3.  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Shape-shifting and tumor suppression by PLZF

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Shape-shifting and tumor suppression by PLZF

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